89,90 Like other B7 family members, B7-H3 mRNA is broadly expressed, but protein expression is restricted. B7-H3 protein can be detected on human myeloid DCs but can only be detected following induction Apoptosis inhibitor with inflammatory stimuli in other leukocyte populations in both humans and mice.87,91,92 The triggering receptor expressed on myeloid cells (TREM)-like transcript 2 (TLT-2) has been identified as a stimulatory counter receptor for B7-H3 on T cells, although this finding is controversial.93,94 Studies with B7-H3-deficient mice support an inhibitory function for B7-H3, displaying elevated T-cell responses in several experimental

settings.91 B7-H3 also appears to have an important function outside the immune system, as B7-H3-deficient mice exhibit reduced bone strength

because of impaired osteoblast differentiation.95 In relation to pregnancy, B7-H3 ICG-001 expression is observed in the villous placenta and changes with advancing gestation, starting within the mesenchymal cells of villi early, and shifting to the syncytiotrophoblast by term.86 The role of B7-H3 in pregnancy is unknown. B7-H4 is another B7 family protein that has been shown to exhibit negative costimulatory activity on T cells, including inhibiting proliferation and cytokine production.96,97 As with the other B7 family members, B7-H4 mRNA is widely distributed, including in human placenta.96 B7-H4 protein expression appears to be restricted to activated hematopoietic cells in humans, but murine B cells constitutively express B7-H496,97 Casein kinase 1 Although the CD28 family member B and T lymphocyte attenuator (BTLA) was initially proposed as a counter-receptor for B7-H4, this no longer seems likely as herpes virus entry mediator (HVEM) is now considered the unique ligand for BTLA.98 T cells express the unknown receptor for B7-H4 following activation.96,97 Studies using B7-H4-deficient

mice suggest that B7-H4 suppresses Th1 immune responses and also inhibits expansion of neutrophils from their progenitors.99,100 Reverse signaling through B7-H4 has also been reported in EBV-transformed B cells, resulting in upregulation of FasL and subsequent apoptosis.101 The role of B7-H4 in pregnancy has not been addressed; however, B7-H4 has been detected on decidual macrophages from term decidua basalis by flow cytometry102 and may therefore potentially affect pregnancy in some manner. B7-H6 is the newest member to the B7 family. It is an activating ligand for the NK receptor, NKp30, and appears to be involved in inducing NK lysis of tumor targets.103 Expression of B7-H6 appears to be highly restricted to tumor cells. In contrast to other B7 family members, B7-H6 mRNA was not detected in any normal tissues, and surface protein expression was absent on both freshly isolated and activated PBMCs.